Treatment switches after CD4 count decline reduce risk of death by 75% in Zambia, Malawi

Carole Leach-Lemens

Published: 09 December 2011

Mortality
was reduced by about 75% among adults experiencing immunological failure
according to the World Health Organization (WHO) criteria who switched to a
second-line regimen compared to those who remained on a failing regimen in two
public sector ART programmes without access to routine viral load monitoring in
Zambia and Malawi,
researchers report in the advance online edition of AIDS.

Additionally
in this collaborative analysis Thomas Gsponer and colleagues on behalf of the
Southern African region of the International epidemiological databases to
evaluate AIDS (IeDEA-SA) showed the less time spent on a failing regimen the
lower the risk of death, HR:0.70 (95%
credible intervals (CI): 0.44-1.09), p=0.11 for each six months of
shorter exposure.

An
estimated 6.6 million people are now getting ART in resource-poor settings. As
access to treatment increases so does the number of people experiencing
treatment failure with a corresponding increase in the use of second-line
treatment regimens.

Cost
and the absence of the necessary laboratory infrastructure preclude the regular
use of viral load monitoring in resource-poor settings, especially in rural
areas.

Without
viral load monitoring immunological (CD4 cell counts) and clinical criteria are
used to determine treatment failure. However, the accuracy of such criteria to
detect virological failure is poor. This may lead to unnecessary switching with
many health care providers reluctant to switch using these criteria. So people
are switched later and at lower CD4 cell counts compared to programmes where
viral load monitoring is available, note the authors.

The
authors chose to examine further the effect of switching to second-line ART on
mortality in settings without viral load monitoring.

All
adult patients experiencing treatment failure according to WHO immunological
criteria from two public sector ART programmes in Lusaka,
Zambia and Lilongwe, Malawi
were included in the analysis. Clinical and immunological monitoring was done
every three to six months. In both sites viral load testing is limited because
of cost and operational difficulties.

Criteria
for inclusion: all patients 16 years of age and over with immunological failure
after January 1, 2004 based on any of the three WHO criteria: 1) CD4 cell
counts staying persistently under 100 cells/mm3 2) a fall of CD4 cell counts
below the baseline count and 3) a fall greater than 50% from the peak value.

Marginal
structural models and inverse probability weighting of switching to compare
mortality between patients who switched and those who did not and between those
who switched immediately and those who switched later were used. The authors
believe this to be the first study of its kind using this model in a
resource-poor setting.

From
2004 to 2009 of the 80,937 patients who started ART, 2411 met the eligibility
criteria and experienced failure; 96.1% (2317) from Zambia
and 3.9% (94) from Zambia.

Of
these 324 (13.4%) were switched to second-line ART during a median of 1.7 years
of follow-up.

Median
CD4 cell count in those who switched was lower at the start of ART and failure
compared to those who did not: 80 cells/mm3 compared to 155 cells/mm3,
p<0.001 and 77 cells/mm3 compared to 146 cells/mm3,
p<0.001, respectively.

In
addition to lower mortality, loss to-follow-up was also lower among people who
switched compared to those who did not: 14.2 (6.8-25.9) compared to 50.5
(43.2-58.5) per 1000 person years, p<0.001, respectively.

After
adjusting for baseline and time-dependent confounders the risk of death among
those who switched to a second-line regimen immediately after failure was
significantly lower than those who remained on a failing regimen (HR 0.25, 95%
CI: 0.09-0.72, p=0.01).

27.2%
(655) patients had at least one viral load measured between six months after
starting ART and immunological failure. Viral load measurement was more common
among those who switched compared to those who did not, but was not
statistically significant.

The
authors note that ideally a randomised clinical trial should be used to
determine the causal effect of switching to second-line treatment among immunologically
failing patients. But they caution this is highly improbable since it raises ethical
concerns.

So
observational data as provided in this study offer the best available evidence
to guide and inform clinical practice and public health decisions on when and
if to switch, they add.

The
authors note that prognostic factors can distort results from observational
studies. Inverse probability of treatment weighting was used to adjust for
confounding by time-updated CD4 cell counts.

The
authors note that while the reduction in death was significant it may have
unknowingly included patients who met the immunological failure criteria but
had an undetectable viral load.

While
two public sector programmes were involved, the authors question how generalisable
their findings are. These programmes are equipped with
electronic medical records systems, have access to regular CD4 cell counts and
are involved in an international collaboration of HIV cohorts. Yet, they
nonetheless follow national guidelines for the public health approach common to
many programmes in the region.

The
authors conclude, “in ART programmes [in sub-Saharan Africa] switching patients
to second-line regimens based on WHO immunological failure criteria appears to
reduce mortality, with the greatest benefit in patients switching immediately
after failure is diagnosed.”

Adding
that targeted viral load may further reduce unnecessary switching and recommend
that future studies “investigate at what CD4 cell count levels patients should
ideally be switched and should examine long-term outcomes including after
second-line failure.”

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